Calpain cleavage and inactivation of the sodium calcium exchanger‐3 occur downstream of A β in A lzheimer's disease

• Published in: Aging cell Vol. 13; no. 1; pp. 49 - 59
• Main Authors: Atherton, Joe, Kurbatskaya, Ksenia, Bondulich, Marie, Croft, Cara L., Garwood, Claire J., Chhabra, Resham, Wray, Selina, Jeromin, Andreas, Hanger, Diane P., Noble, Wendy
• Format: Journal Article
• Language: English
• Published: 01-02-2014
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12148

Summary
Alzheimer's disease (
AD
) is a neurodegenerative disorder characterized by pathological deposits of β‐amyloid (
A
β) in senile plaques, intracellular neurofibrillary tangles (
NFT
s) comprising hyperphosphorylated aggregated tau, synaptic dysfunction and neuronal death. Substantial evidence indicates that disrupted neuronal calcium homeostasis is an early event in
AD
that could mediate synaptic dysfunction and neuronal toxicity. Sodium calcium exchangers (
NCX
s) play important roles in regulating intracellular calcium, and accumulating data suggests that reduced
NCX
function, following aberrant proteolytic cleavage of these exchangers, may contribute to neurodegeneration. Here, we show that elevated calpain, but not caspase‐3, activity is a prominent feature of
AD
brain. In addition, we observe increased calpain‐mediated cleavage of
NCX
3, but not a related family member
NCX
1, in
AD
brain relative to unaffected tissue and that from other neurodegenerative conditions. Moreover, the extent of
NCX
3 proteolysis correlated significantly with amounts of
A
β1–42. We also show that exposure of primary cortical neurons to oligomeric
A
β1–42 results in calpain‐dependent cleavage of
NCX
3, and we demonstrate that loss of
NCX
3 function is associated with
A
β toxicity. Our findings suggest that
A
β mediates calpain cleavage of
NCX
3 in
AD
brain and therefore that reduced
NCX
3 activity could contribute to the sustained increases in intraneuronal calcium concentrations that are associated with synaptic and neuronal dysfunction in
AD
.